We have continued to explore the role that reactive oxygen species (ROS)play in signal transduction pathways. We have shown that a variety of growth factors and cytokines induce the generation of ROS following ligand binding. Our studies suggest that the pathway leading to ROS generation involves the activation of the small GTP-binding proteins ras and rac1. This has led us to explore fully the role of these proteins, and in particular, their role in vascular biology. We have also explored the role that ROS play in apoptosis, and more recently in replicative senescence. Our current focus is on how small GTPases regulate the cellular redox state and the identification of protein targets of oxidants. In the last year we have been able to demonstrate that inhibition of rac proteins by expression of a dominant negative form of rac1, inhibits cell death that occurs following hypoxic/reoxygenation (Kim, et al. J. Clin. Invest., 1998, 101:1821-1826). Similarly, we have shown that in normal cells, expression of an activated ras gene induces senescence by a redox-dependent pathway (Lee, et al., J. Biol. Chem., submitted). We have also explored the role of reactive oxygen species in cardiac myocyte apoptosis (Tanaka, et al., J. Biol. Chem., 1998; 273:25922-25928). These results, along with ongoing studies will hopefully delineate a role for oxidant-dependent signal transduction.